The present invention relates to compounds of formula (I), which are useful for treating diseases or conditions caused by or exacerbated by P2X receptor activity, pharmaceutical compositions containing compounds of formula (I) and methods of treatment using compounds of formula (I).
P2X receptors function as homomultimeric cation-permeable ion channels and, in some cases, as heteromeric channels consisting of two different P2X receptor subtypes ((Lewis et al., Nature 377:432-435 (1995); Le et al., The Journal of Neuroscience, 18 (1998) 7152-7159, Torres et al., Molecular Pharmacology, 54 (1998) 989-993). At least one pair of P2X receptor subtypes, P2X2 and P2X3, functions as a heteromeric channel in rat nodose ganglion neurons where it exhibits distinct pharmacological and electrophysiological properties (Lewis et al., Nature 377:432-435 1995).
With respect to individual receptors, the rat P2X2 containing receptor is expressed in the spinal cord, and in the nodose and dorsal root ganglia (Brake et al., Nature 371:519-523 (1994)), while rat P2X3 containing receptor expression is found primarily in a subset of neurons of the sensory ganglia (Chen et al., Nature 377:428-430 (1995); Vulchanova et al., Neuropharmacol. 36:1229-1242 (1997)). The distribution of both receptors is consistent with a role in pain transmission. The P2X2 and P2X3 subunits form functional channels when expressed alone, and can also form a functional heteromultimeric channel that has properties similar to currents seen in native sensory channels when co-expressed (Lewis et al., Nature 377:432-435 (1995)). Evidence from studies in rat nodose ganglia indicate that both P2X2/P2X3 heteromeric channels and P2X2 homomeric channels contribute to adenosine triphosphate-induced currents (Virginio et al., J Physiol (Lond) 510:27-35 (1998); Thomas et al., J Physiol (Lond) 509 (Pt 2):411-417 (1998)); Vulchanova et al., Proc Natl Acad Sci U S A 93:8063-8067 (1996);; Simon et al., Mol Pharmacol 52:237-248 (1997)).
ATP, which activates P2X2, P2X3, and P2X2/P2X3 containing receptors, functions as an excitatory neurotransmitter in the spinal cord dorsal horn and in primary afferents from sensory ganglia (Holton and Holton, J. Physiol. (Lond.) 126:124-140 (1954)). ATP-induced activation of P2X receptors on dorsal root ganglion nerve terminals in the spinal cord stimulates the release of glutamate, a key neurotransmitter involved in nociceptive signaling (Gu and MacDermott, Nature 389:749-753 (1997)). Thus, ATP released from damaged cells can evoke pain by activating P2X2, P2X3, or P2X2/P2X3 containing receptors on nociceptive nerve endings of sensory nerves. This is consistent with the induction of pain by intradermally applied ATP in the human blister-base model (Bleehen, Br J Pharmacol 62:573-577 (1978)); the identification of P2X3 containing receptors on nociceptive neurons in the tooth pulp (Cook et al., Nature 387:505-508 (1997)); and with reports that P2X antagonists are analgesic in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350:618-625 (1994)). This evidence suggests that P2X2 and P2X3 function in nociception, and that modulators of these human P2X receptors are useful as analgesics.
It has been recently demonstrated that P2X3 receptor gene disruption results in a diminished sensitivity to noxious chemical stimuli and reduced pain (Cesare et al., Drug Dev. Res. 50: S01-02 (2000); Cockayne et al., Drug Dev. Res. 50: 005 (2000)). P2X3 containing receptor knock-out mice also exhibited a marked urinary bladder hyporeflexia upon cystometric evaluation, suggesting that P2X3 antagonists have utility for treating bladder overactivity. P2X3 knock-out mice had decreased voiding frequency, increased voiding volume, but normal bladder pressure. It has been proposed that ATP acts as a physiological regulator of sensory neurotransmission in visceral hollow organs such as bladder (Namasivayam et al., Brit. J. Urol. Int. 84L 854-860. (1999), and P2X3 containing receptors localized on the basal surface of the urothelium. The urology data on the P2X3 knock-out mice suggest that P2X3 plays a major role in modulating the volume threshold for activation of micturition and that P2X3 antagonists have therapeutic utility for urinary incontinence.
The nociceptive effects of exogenously administered ATP and P2X containing receptor agonists have also been demonstrated in laboratory animals (Bland-Ward and Humphrey, 1997; Hamilton et al., 1999). The peripheral nociceptive actions of P2X activation and stimulation of spinal P2X containing receptors also contribute to nociception as indicated by the ability of intrathecally (i.t.) administered P2 receptor agonists to increase sensitivity to acute and persistent noxious stimuli in rodents (Driessen et al., 1994; Tsuda et al., 1999a; 1999b).
The utility of available purinergic ligands to evaluate the role of individual P2 receptor subtypes in mammalian physiology has been complicated by the susceptibility of P2 receptor agonists to undergo enzymatic degradation, and by the lack of P2 receptor subtype-selective agonists and antagonists (King et al., 1999; Ralevic and Burnstock, 1998).
Since subtype-selective ligands for the individual P2 receptors have yet to be identified, efforts to elucidate the specific P2X containing receptor subtypes involved in the transmission of nociceptive signals has been largely based on receptor localization and functional studies using immunohistochemical techniques. These studies have shown that both the homomeric P2X3 and heteromeric P2X2/3 containing receptor subtypes are selectively localized to the central and peripheral terminals of small diameter sensory neurons (Chen et al., 1995; Lewis et al., 1995; Vulchanova et al., 1997; 1998). Further, recent data has shown that P2X3 specific immunoreactivity is significantly increased in both the injured dorsal root ganglion and in the ipsalateral spinal dorsal horn following chronic constriction injury of the rat sciatic nerve (Novakovic et al., 1999).
The functional and immunohistochemical localization of P2X3 and/or P2X2/3 containing receptors on sensory nerves indicates that these P2X containing receptors have a primary role in mediating the nociceptive effects of exogenous ATP. Thus, compounds which block or inhibit activation of P2X3 containing receptors serve to block the pain stimulus. Antagonists of the P2X3 homomeric channel and/or the P2X2/P2X3 heteromeric channel could successfully block the transmission of pain.
The compounds of the present invention are novel P2X3 and P2X2/3 antagonists, having utility in treating pain as well as in treating bladder overactivity and urinary incontinence.
The present invention discloses trisubstituted-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]benzamides compounds, a method for controlling pain in mammals, and pharmaceutical compositions including those compounds. More particularly, the present invention is directed to compounds of formula (I): 
or pharmaceutically acceptable salts or prodrugs thereof, wherein
A1 and A2 are each independently selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NRARB)carbonyl, (NRCS(O)2RD)carbonyl, xe2x80x94S(O)2OH, or tetrazolyl; or
A1 and A2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto or oxo;
A3 is selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NRARB)carbonyl, (NRCS(O)2RD)carbonyl, xe2x80x94S(O)2OH, or tetrazolyl;
A4, A5, A6 and A7 are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxy, hydroxyalkyl, nitro, xe2x80x94NRERF, or (NRERF)carbonyl;
A8, A9, A10 and A11 are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxy, hydroxyalkyl, xe2x80x94NRERF, (NRERF)carbonyl, or oxo;
RA and RB are each independently selected from hydrogen, alkyl, or cyano;
RC is selected from hydrogen or alkyl;
RD is selected from alkoxy, alkyl, aryl, arylalkoxy, arylalkyl, haloalkoxy, or haloalkyl;
RE and RF are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, or hydroxyalkyl;
L1 is selected from alkenylene, alkylene, alkynylene, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, or xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94 wherein each group is drawn with the left end attached to N and the right end attached to R1;
m is an integer 0-10;
n is an integer 0-10;
R1 is selected from aryl, cycloalkenyl, cycloalkyl, or heterocycle;
L2 is absent or selected from a covalent bond, alkenylene, alkylene, alkynylene, xe2x80x94(CH2)pO(CH2)qxe2x80x94, (CH2)pS(CH2)qxe2x80x94, (CH2)pC(O)(CH2)qxe2x80x94, or xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94 wherein each group is drawn with the left end attached to R1 and the right end attached to R2;
p is an integer 0-10;
q is an integer 0-10; and
R2 is absent or selected from aryl, cycloalkenyl, cycloalkyl, or heterocycle.
The principle embodiment of the present invention is directed to compounds of formula (I): 
or pharmaceutically acceptable salts or prodrugs thereof, wherein
A1 and A2 are each independently selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NRARB)carbonyl, (NRCS(O)2RD)carbonyl, xe2x80x94S(O)2OH, or tetrazolyl;
or
A1 and A2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto or oxo;
A3 is selected from alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NRARB)carbonyl, (NRCS(O)2RD)carbonyl, xe2x80x94S(O)2OH, or tetrazolyl;
A4, A5, A6 and A7 are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxy, hydroxyalkyl, nitro, xe2x80x94NRERF, or (NRERF)carbonyl;
A8, A9, A10 and A11 are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxy, hydroxyalkyl, xe2x80x94NRERF, (NRERF)carbonyl, or oxo;
RA and RB are each independently selected from hydrogen, alkyl, or cyano;
RC is selected from hydrogen or alkyl;
RD is selected from alkoxy, alkyl, aryl, arylalkoxy, arylalkyl, haloalkoxy, or haloalkyl;
RE and RF are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, or hydroxyalkyl;
L1 is selected from alkenylene, alkylene, alkynylene, xe2x80x94(CH2)mO(CH2)nxe2x80x94, xe2x80x94(CH2)mS(CH2)nxe2x80x94, or xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94 wherein each group is drawn with the left end attached to N and the right end attached to R1;
m is an integer 0-10;
n is an integer 0-10;
R1 is selected from aryl, cycloalkenyl, cycloalkyl, or heterocycle;
L2 is absent or selected from a covalent bond, alkenylene, alkylene, alkynylene, xe2x80x94(CH2)pO(CH2)qxe2x80x94, xe2x80x94(CH2)pS(CH2)qxe2x80x94, xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94, or xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94 wherein each group is drawn with the left end attached to R1 and the right end attached to R2;
p is an integer 0-10;
q is an integer 0-10; and
R2 is absent or selected from aryl, cycloalkenyl, cycloalkyl, or heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from alkoxycarbonyl, carboxy, hydroxy, (NRARB)carbonyl, (NRCS(O)2RD)carbonyl, and xe2x80x94S(O)2OH; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; RA and RB are each independently selected from hydrogen, alkyl, and cyano; L1 is selected from alkylene and xe2x80x94(CH2)mO(CH2)nxe2x80x94; R1 is selected from aryl, cycloalkyl and heterocycle; L2 is absent or selected from a covalent bond, alkylene, xe2x80x94(CH2)pO(CH2)qxe2x80x94, xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94, (CH2)pC(OH)(CH2)qxe2x80x94, xe2x80x94(CH2)pS(CH2)qxe2x80x94, and xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; P is 0; q is an integer 0-1; R2 is absent or selected from aryl, cycloalkenyl, cycloalkyl and heterocycle; and RC and RD are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto and oxo; and A3, A4, A5, A6, A7, A8, A9, A10, A11, L1, R1, L2 and R2 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is absent; R2 is absent; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is absent; R2 is absent; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydogen; L1 is alkylene wherein said is alkylene selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2CH(CH3)xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is absent; and R2 is absent; and RE, RF, and REE are as defined as in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is fluorenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, nitro, oxo, or xe2x80x94NRERF; L2 is absent; R2 is absent; and RE, RF, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is fluorenyl substituted with 0 or 1 substituent selected from hydroxy and oxo; L2 is absent; and R2 is absent.
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is a covalent bond; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is a covalent bond; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is a covalent bond; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined as in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is substituted with 0, 1, or 2 substituents selected from mercapto and oxo; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10, and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is a covalent bond; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined as in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is a covalent bond; R2 is heterocycle; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is a covalent bond; R2 is heterocycle wherein said heterocycle is selected from azetidinyl, azepanyl, aziridinyl, furyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl and thienyl wherein said heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, arylalkoxycarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is a covalent bond; and R2 is heterocycle wherein said heterocycle is selected from pyridinyl, pyrrolidinyl, and thienyl wherein said heterocycle is substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, nitro, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94NRERF; and RA, RB, RC, RE, RF, REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is alkylene; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is alkylene; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x80x94NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94;
R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from alkoxycarbonyl, carboxy, hydroxy, (NRARB)carbonyl, or xe2x80x94S(O)2OH; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RD, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; RD is selected from alkyl or aryl; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, and xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x80x94NOREE, and xe2x80x94NRERF; RD is selected from alkyl or aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, xe2x80x94NRERF, and xe2x80x94N(RA)C(O)NRBRC; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; RD is heterocycle; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
XX In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (RCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; RD is heterocycle wherein said heterocycle is pyridinyl and thienyl wherein said heterocycle is substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, nitro, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94NRERF; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; RD is arylalkyl; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1 and A2 are each independently selected from carboxy or (NRCS(O)2RD)carbonyl wherein one of A1 or A2 is (NRCS(O)2RD)carbonyl; A3 is carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; RD is arylalkyl wherein the aryl of arylalkyl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 1; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is cycloalkyl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is cycloalkyl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, p and q are as defined in formula (I); and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x80x94NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is cycloalkyl; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is cycloalkenyl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is cycloalkenyl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are defined in formula (I); and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is cycloalkenyl; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is heterocycle; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; R2 is heterocycle wherein heterocycle is selected from furyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl wherein said heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, arylalkoxycarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p, and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is heterocycle wherein heterocycle is selected from pyridinyl or pyrimidinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, nitro, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94NRERF; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pS(CH2)qxe2x80x94; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pS(CH2)qxe2x80x94; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A9 A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pS(CH2)qxe2x80x94; p is 0; q is 0; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pC(O)(CH2)qxe2x80x94; p is 0; q is 0; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pC(OH)(CH2)qxe2x80x94; R2 is aryl; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pC(OH)(CH2)qxe2x80x94; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A5, A6, A7, A8, A9, A10 A11, p, and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, As, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pC(OH)(CH2)pC(OH)(CH2)qxe2x80x94; p is 0; q is 0; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x80x94NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; R2 is aryl; and A1, A2, A3, A4, A5, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; R2 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p, and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; p is 0; q is an integer 0-1; and R2 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is aryl; L2 is xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; R2 is heterocycle; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein said alkylene is xe2x80x94CH2xe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is xe2x80x94(CH2)pCHxe2x95x90NO(CH2)qxe2x80x94; p is 0; q is 0; and R2 is heterocycle wherein said heterocycle is pyranyl substituted with 0,1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, nitro, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94NRERF; and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is cycloalkyl; L2 is absent; R2 is absent; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, p and q are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is xe2x80x94CH2xe2x80x94; R1 is cycloalkyl; L2 is absent; and R2 is absent.
In another embodiment, compounds of the present invention have formula (I) wherein L1 is xe2x80x94(CH2)mO(CH2)nxe2x80x94; R1 is aryl; L2 is absent; R2 is absent; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, and n are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is xe2x80x94(CH2)nO(CH2)nxe2x80x94; R1 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is absent; R2 is absent; and RA, RB, RC, RE, RF, REE, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 A11, m, and n are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is xe2x80x94(CH2)mO(CH2)nxe2x80x94; m is an integer 2-4; n is 0; R1 is aryl wherein said aryl is phenyl with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, methylenedioxy, nitro, xe2x80x94CHxe2x95x90NOREE, or xe2x80x94NRERF; L2 is absent; R2 is absent; and RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is heterocycle; L2 is absent; R2 is absent; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein L1 is alkylene; R1 is heterocycle wherein said heterocycle is selected from furyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thienyl wherein said heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, arylalkoxycarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94CHxe2x95x90NOREE; L2 is absent; R2 is absent; and A1, A2, A3, A4, A5, A6, A7, A8, A9, A10 and A11 are as defined in formula (I); and RA, RB, RC, RE, RF, and REE are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A1, A2 and A3 are each carboxy; A4, A5, A6, A7, A8, A9, A10 and A11 are each hydrogen; L1 is alkylene wherein alkylene is xe2x80x94CH2xe2x80x94; R1 is heterocycle wherein said heterocycle is thienyl substituted with 0, 1, or 2 substituents selected from alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkyl, alkylthio, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxyalkyl, nitro, xe2x80x94N(RA)C(O)NRBRC, or xe2x80x94NRERF; L2 is absent; R2 is absent; and RE, RF, and REE are as defined in formula (I).
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
Definition of Terms
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term xe2x80x9calkenylxe2x80x9d as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
The term xe2x80x9calkenylenexe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond. Representative examples of alkenylene include, but are not limited to, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CH2CH2xe2x80x94, and xe2x80x94CHxe2x95x90C(CH3)CH2xe2x80x94.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein, means an alkenyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy and 3-butenyloxy.
The term xe2x80x9calkoxyxe2x80x9d as used herein, means an alkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein, means an alkoxy group, as defined herein, is appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein, means an alkoxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein, means an alkoxy group, as defined herein, is appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein, means an alkoxycarbonyl group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
The term xe2x80x9calkoxysulfonylxe2x80x9d as used herein, means an alkoxy group, as defined herein, is appended appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
The term xe2x80x9calkylxe2x80x9d as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term xe2x80x9calkylcarbonylxe2x80x9d as used herein, means an alkyl group, as defined herein, is appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term xe2x80x9calkylcarbonylalkylxe2x80x9d as used herein, means an alkylcarbonyl group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
The term xe2x80x9calkylcarbonyloxyxe2x80x9d as used herein, means an alkylcarbonyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)xe2x80x94 xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, and xe2x80x94CH2CH(CH3)CH2xe2x80x94.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein, means an alkyl group, as defined herein, is appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term xe2x80x9calkylthioxe2x80x9d as used herein, means an alkyl group, as defined herein, is appended to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
The term xe2x80x9calkylthioalkylxe2x80x9d as used herein, means an alkylthio group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited, methylsulfanylmethyl and 2-(ethylsulfanyl)ethyl.
The term xe2x80x9calkynylxe2x80x9d as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term xe2x80x9calkynylenexe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one triple bond. Representative examples of alkynylene include, but are not limited to, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(CH3)CH2Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x89xa1CCH2xe2x80x94, and xe2x80x94Cxe2x95x90CCH(CH3)CH2xe2x80x94.
The term xe2x80x9calkynyloxy,xe2x80x9d as used herein, means an alkynyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of alkynyloxy include, but are not limited to, 2-propynyloxy and 2-butynyloxy.
The term xe2x80x9carylxe2x80x9d as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system wherein one or more of the fused rings is a phenyl group. Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
The aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, and xe2x80x94CHxe2x95x90NOREE wherein REE is selected from hydrogen and alkyl, as defined herein.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein, means an aryl group, as defined herein, is appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
The term xe2x80x9carylalkoxycarbonylxe2x80x9d as used herein, means an arylalkoxy group, as defined herein, is appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl.
The term xe2x80x9ccarbonylxe2x80x9d as used herein, means a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxyxe2x80x9d as used herein, means a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein, means a carboxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
The term xe2x80x9ccyanoxe2x80x9d as used herein, means a xe2x80x94CN group.
The term xe2x80x9ccyanoalkylxe2x80x9d as used herein, means a cyano group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein, means a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane and tricyclo[3.3.1.13,7]decane (adamantane).
The cycloalkyl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl and xe2x80x94CHxe2x95x90NOREE wherein REE is selected from hydrogen and alkyl, as defined herein.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein, means a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.
The cycloalkenyl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl and xe2x80x94CHxe2x95x90NOREE wherein REE is selected from hydrogen and alkyl, as defined herein.
The term xe2x80x9cethylenedioxyxe2x80x9d as used herein, refers to a xe2x80x94O(CH2)2Oxe2x80x94 group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
The term xe2x80x9cformylxe2x80x9d as used herein, means a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein, means xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein, means at least one halogen, as defined herein, is appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term xe2x80x9chaloalkylxe2x80x9d as used herein, means at least one halogen, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term xe2x80x9chaloalkylthioxe2x80x9d as used herein, means a haloalkyl group, as defined herein, is appended to the parent molecular moiety through a sulfur atom. Representative examples of haloalkylthio include, but are not limited to, (trifluoromethyl)sulfanyl and (pentafluoroethyl)sulfanyl.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d as used herein, means a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl, indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridinyl. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl, carbolinyl, dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, naphtho[2,3-b]furan, naphtho[2,3-b]thienyl, phenazinyl, phenothiazinyl, phenoxazinyl, thianthrenyl, thioxanthenyl and xanthenyl.
The heterocycles of this invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, alkynyloxy, arylalkoxycarbonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, methylenedioxy, nitro, oxo, xe2x80x94NRERF, (NRERF)carbonyl, xe2x80x94N(RA)C(O)NRBRC, and xe2x80x94CHxe2x95x90NOREE wherein REE is selected from hydrogen and alkyl, as defined herein.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, means an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, 1,3-dihydroxypropyl, 1,2-dihydroxypropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.
The term xe2x80x9cmercaptoxe2x80x9d as used herein, means a xe2x80x94SH group.
The term xe2x80x9cmethylenedioxyxe2x80x9d as used herein, means a xe2x80x94OC(Z3)(Z4)Oxe2x80x94 group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms. Z3 and Z4 are each independently selected from hydrogen or alkyl or Z3 and Z4 together with the carbon atom to which they are attached form a 5 or 6 membered cycloalkyl group, as defined herein.
The term xe2x80x9cnitroxe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9cxe2x80x94NRARBxe2x80x9d as used herein, means two groups, RA and RB, are appended to the parent molecular moiety through a nitrogen atom. RA and RB are each independently selected from hydrogen, alkyl and cyano. Representative examples of xe2x80x94NRARB include, but are not limited to, amino, methylamino, dimethylamino and cyanoamino.
The term xe2x80x9c(NRARB)carbonylxe2x80x9d as used herein, means a xe2x80x94NRARB group, as defined herein, is appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, (cyanoamino)carbonyl and (ethylmethylamino)carbonyl.
The term xe2x80x9cxe2x80x94NRERFxe2x80x9d as used herein, means two groups, RE and RF, are appended to the parent molecular moiety through a nitrogen atom. RE and RF are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, and hydroxyalkyl. Representative examples of xe2x80x94NRERF include, but are not limited to, amino, acetylamino, methylamino, dimethylamino, ethylmethylamino, (2,3-dihydoxypropyl)amino, and formylamino.
The term xe2x80x9c(NRERF)carbonylxe2x80x9d as used herein, means a xe2x80x94NRERF group, as defined herein, is appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRERF)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl and (ethylmethylamino)carbonyl.
The term xe2x80x9cxe2x80x94NRCS(O)2RDxe2x80x9d is used herein means RD appended to the parent molecular moiety through a sulfonyl group, the sulfonyl group with is further appended to the parent molecular moiety through an amino group as defined herein. Examples of xe2x80x94NRCS(O)2RD include, but not limited to, arylsulfonylamino wherein aryl is substituted or unsubstituted phenyl.
The term xe2x80x9c(NRCS(O)2RD)carbonylxe2x80x9d is used herein means a xe2x80x94NRCS(O)2RD group appended to the parent molecular moiety through a carbonyl group.
The term xe2x80x9coxoxe2x80x9d as used herein, means a xe2x95x90O moiety.
The term xe2x80x9csulfonylxe2x80x9d as used herein, means a xe2x80x94SO2xe2x80x94 group.
Compounds of the present invention were determined to be P2X3 and P2X2/3 antagonists based on their ability to inhibit increases in cytosolic Ca2+ concentration elicited by the P2X receptor agonist xcex1xcex2-methyleneATP (xcex1xcex2-meATP; Sigma, St. Louis, Mo.) as described in Bianchi et al. (1999). The fluorescent Ca2+ chelating dye fluo-4 was used as an indicator of the relative levels of intracellular Ca2+ in a 96-well format using a Fluorescence Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, Calif.). Cells expressing recombinant human P2X3 or P2X2/3 containing receptors were grown to confluence and plated in 96-well black-walled tissue culture plates approximately 18 hours prior to the experiment. One to two hours before the assay, cells were loaded with fluo-4 AM (2.28 xcexcM; Molecular Probes, Eugene, Oreg.) in D-PBS and maintained in a dark environment at room temperature. Immediately before the assay, each plate was washed twice with 250 xcexcl D-PBS per well to remove extracellular fluo-4 AM and then 100 xcexcl D-PBS was added to the wells. Two 50 xcexcl additions of compounds (4xc3x97 concentration prepared in D-PBS) were made to the cells during each experiment. The first addition consisting of test antagonist was made and incubation continued for 3 minutes before the addition of the agonist xcex1xcex2-meATP, measurement continued for 3 minutes after this final addition. Fluorescence data was collected at 1 or 5 second intervals throughout the course of each experiment and were analyzed based on the peak increase in relative fluorescence units compared with basal fluorescence. Antagonist concentration-response data, expressed as a percentage of the maximal xcex1xcex2-meATP response in the absence of test antagonist, were analyzed using GraphPad Prism (San Diego, Calif.).
The compounds of the present invention were found to be antagonists of the P2X3 containing receptor with potencies from 5000 nM to 0.5 nM. In a preferred range, the compounds of the present invention antagonized P2X3 containing receptors with potencies from 500 nM to 0.5 nM. In a more preferred range, the compounds of the present invention antagonized P2X3 containing receptors with potencies from 50 nM to 0.5 nM.
Additionally, the compounds of the present invention were found to be antagonists of the P2X2/3 containing receptors with potencies from 4800 nM to 0.5 nM. In a preferred range, the compounds of the present invention antagonized P2X2/3 containing receptors with potencies from 500 nM to 0.5 nM. In a more preferred range, the compounds of the present invention antagonized P2X2/3 containing receptors with potencies from 50 nM to 0.5 nM.
Following a 30-minute acclimation period to individual clear observation cages, 50 xcexcl of a 5% formalin solution was injected subcutaneously (s.c.) into the dorsal aspect of the right hindpaw of rats (male Sprague-Dawley, 200-300 g) were then returned to the observation cages, which were suspended above mirrors. Rats, six per group, were observed for either a continuous period of 60 minutes or for periods of time corresponding to phase 1 and phase 2 of the formalin test (Abbott et al., Pain, 60 (1995) 91-102). Phase 1 of the formalin test was defined as the period of time immediately following injection of formalin until 10 minutes after the formalin injection. Effects on Phase 2 of the formalin test were determined by monitoring for the 20 minute period of time from 30 to 50 minutes following formalin injection. Nociceptive behaviors were recorded from animals during the session by observing each animal for one 60 second observation period during each 5 minute interval. Nociceptive behaviors recorded included flinching, licking or biting the injected paw.
The compounds of the present invention were found to have antinociceptive effects with potencies from 100 xcexcmol/kg to 15 xcexcmol/kg.
The in vitro and in vivo data demonstrates that compounds of the present invention antagonize the P2X3 containing receptor, antagonize the P2X2/3 containing receptor, and are useful for treating pain. Compounds of the present invention are thus useful for ameliorating or preventing additional disorders that are affected by the P2X3 and/or the P2X2/3 containing receptors such as bladder overactivity and urinary incontinence.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.01 to about 100 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.1 to about 25 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term xe2x80x9cparenterally,xe2x80x9d as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Compounds of the present invention that are formed by in vivo conversion of a different compound that was administered to a mammal are intended to be included within the scope of the present invention.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
The compounds of the invention, including but not limited to those specified in the examples, are P2X3 and P2X2/P2X3 containing receptor antagonists in mammals. As P2X3 and P2X2/P2X3 containing receptor antagonists, the compounds of the present invention are useful for the treatment and prevention of disorders such as bladder overactivity, urinary incontinence or pain.
The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat bladder overactivity or urinary incontinence is demonstrated by Namasivayam et al., Brit. J. Urol. Int. 84L 854-860. (1999).
The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat pain is demonstrated by Cesare et al., Drug Dev. Res. 50: S01-02 (2000); Cockayne et al., Drug Dev. Res. 50: 005 (2000); Bleehen, Br. J. Pharmacol. 62:573-577 (1978); Cook et al., Nature 387:505-508 (1997); and Driessen and Starke, Naunyn Schmiedebergs Arch. Pharmacol. 350:618-625 (1994).
Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: DCC for 1,3-dicyclohexylcarbodiimide, DME for dimethoxyethane, DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide, EDCI or EDC for 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, LAH for lithium aluminum hydride, RP-HPLC for reverse phase-high pressure liquid chromatography and THF for tetrahydrofuran.
The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes and Examples which illustrate a means by which the compounds of the present invention can be prepared. 
Benzenetricarboxylic acids of general formula (4), wherein A4, A5, A6, A7, A8, A9, A10, A11, R1, R2 and L2 are as defined in formula (I), may be prepared as described in Scheme 1. (1S)-1,2,3,4-Tetrahydro-1-naphthalenylamines of general formula (1), purchased commercially or prepared using standard chemistry known to those in the art, may be treated with aldehydes of general formula (2) and a hydride source such as sodium borohydride in a solvent such as ethanol to provide secondary amines of general formula (3). Secondary amines of general formula (3) may be treated with 1,2,4,5-benzenetetracarboxylic dianhydride and an organic base such as triethylamine and after a period of 4-72 hours a base in water such as sodium carbonate/water may be added to the reaction mixture to provide benzenetricarboxylic acids of general formula (4). 
An alternate method of preparing benzenetricarboxylic acids of general formula (4), wherein A4, A5, A6, A7, A8, A9, A10, A11, R1, R2 and L2 are as defined in formula (I), may be used as described in Scheme 2. (1S)-1,2,3,4-Tetrahydro-1-naphthalenylamines of general formula (1) may be coupled with acids of general formula (6) using standard coupling conditions known to those in the art such. Carbodiimides such as DCC or EDCI may be used or other coupling conditions may be used such as thionyl chloride or chloroformates to provide amides of general formula (7). Amides of general formula (7) may be treated with borane-tetrahyrofuran complex or lithium aluminum hydride to provide secondary amines of general formula (3). Secondary amines of general formula (3) may be processed as described in Scheme 1 to provide benzenetricarboxylic acids of general formula (4). 
Amides of general formula (10) and (11), wherein A4, A5, A6, A7, A8, A9, A10, A11, R1, R2, L1, L2, RA and RB are as defined in formula (I), may be prepared as described in Scheme 2. Secondary amines of general formula (3) may be treated with 1,2,4,5-benzenetetracarboxylic dianhydride and an organic base such as triethylamine and after a period of 4-72 hours an amine of general formula (9) may be added to the reaction mixture to provide amides of general formula (10) and (11). Esters may also be prepared in similar fashion except that an alcohol is added after the 4-72 hour period instead of an amine. 
1,3-Dioxo-1,3-dihydro-2-benzothiophene-5-carboxylic acids of general formula (13), wherein A4, A5, A6, A7, A8, A9, A10, A11, R1, R2, L1 and L2 are defined in formula (I), may be prepared as described in Scheme 4. Secondary amines of general formula (3) may be treated with 1,2,4,5-benzenetetracarboxylic dianhydride and an organic base such as triethylamine at xe2x88x9278xc2x0 C. and allowed to warm to ambient temperature and stir for 4-72 hours. The reaction mixture may then be recooled to xe2x88x9278xc2x0 C. and treated with sodium sulfide nonahydrate followed by aqueous acid to provide 1,3-dioxo-1,3-dihydro-2-benzothiophene-5-carboxylic acids of general formula (13).
The following Examples are intended as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.